Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by its interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: A1, A2a, A2b and A3. A1 and A3 are high-affinity, inhibiting the activity of the enzyme adenylate cyclase, and A2a and Ab are low-affinity, stimulating the activity of the same enzyme. Analogs of adenosine able to interact as antagonists with the A1, A2a, A2b and A3 receptors have also been identified.
Selective antagonists for the A2a receptor are of pharmacological interest because of their reduced level of side effects. In the central nervous system, A2a antagonists can have antidepressant properties and stimulate cognitive functions. Moreover, data has shown that A2a receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2a antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, and psychoses of organic origin.
Adenosine A2a receptor antagonists have been disclosed as being useful in the treatment or prevention of Extra Pyramidal Syndrome (EPS), dystonia, restless leg syndrome (RLS) or periodic limb movement in sleep (PLMS) in International Publication No. WO 2005/044245, and have been disclosed as being useful in the treatment of attention deficit hyperactivity disorder (ADHD) in International Publication No. WO 2002/055083.